Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of ...drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions.
Bacteria belonging to the Rhodococcus genus are frequent components of microbial communities in diverse natural environments. Some rhodococcal species exhibit the outstanding ability to produce ...significant amounts of triacylglycerols (TAG) (>20% of cellular dry weight) in the presence of an excess of the carbon source and limitation of the nitrogen source. For this reason, they can be considered as oleaginous microorganisms. As occurs as well in eukaryotic single-cell oil (SCO) producers, these bacteria possess specific physiological properties and molecular mechanisms that differentiate them from other microorganisms unable to synthesize TAG. In this review, we summarized several of the well-characterized molecular mechanisms that enable oleaginous rhodococci to produce significant amounts of SCO. Furthermore, we highlighted the ability of these microorganisms to degrade a wide range of carbon sources coupled to lipogenesis. The qualitative and quantitative oil production by rhodococci from diverse industrial wastes has also been included. Finally, we summarized the genetic and metabolic approaches applied to oleaginous rhodococci to improve SCO production. This review provides a comprehensive and integrating vision on the potential of oleaginous rhodococci to be considered as microbial biofactories for microbial oil production.
Infectious diseases are caused by pathogenic microorganisms and are often severe. Time to fully characterize an infectious agent after sampling and to find the right antibiotic and dose are important ...factors in the overall success of a patient's treatment. Previous results suggest that a nanomotion detection method could be a convenient tool for reducing antibiotic sensitivity characterization time to several hours. Here, the application of the method for slow‐growing bacteria is demonstrated, taking Bordetella pertussis strains as a model. A low‐cost nanomotion device is able to characterize B. pertussis sensitivity against specific antibiotics within several hours, instead of days, as it is still the case with conventional growth‐based techniques. It can discriminate between resistant and susceptible B. pertussis strains, based on the changes of the sensor's signal before and after the antibiotic addition. Furthermore, minimum inhibitory and bactericidal concentrations of clinically applied antibiotics are compared using both techniques and the suggested similarity is discussed.
Infectious diseases are one of the most important causes of human mortality worldwide. Therefore, rapid detection and identification of microbial pathogens are mandatory in order to treat patients appropriately. The article presents the application of a nanomotion sensor for slow‐growing bacterial pathogens for testing their antibiotic susceptibility in a much faster way than conventional tests.
After myocardial infarction (MI), extensive remodelling of the extracellular matrix contributes to scar formation. While aiming to preserve tissue integrity, this fibrotic response is also associated ...with adverse events, including a markedly increased risk of heart failure, ventricular arrhythmias, and sudden cardiac death. Cardiac fibrosis is characterized by extensive deposition of collagen and also by increased stiffness as a consequence of enhanced collagen cross-linking. Members of the lysyl oxidase (LOX) family of enzymes are responsible for the formation of collagen cross-links. This study investigates the contribution of LOX family members to the heart response to MI.
Experimental MI was induced in C57BL/6 mice by permanent ligation of the left anterior descending coronary artery. The expression of LOX isoforms (LOX and LOXL1-4) was strongly increased upon MI, and this response was accompanied by a significant accumulation of mature collagen fibres in the infarcted area. LOX expression was observed in areas of extensive remodelling, partially overlapping with α-smooth muscle actin-expressing myofibroblasts. Tumour growth factor-β as well as hypoxia-activated pathways contributed to the induction of LOX expression in cardiac fibroblasts. Finally, in vivo post-infarction treatment with the broadband LOX inhibitor β-aminopropionitrile or, selectively, with a neutralizing antibody against the canonical LOX isoform attenuated collagen accumulation and maturation and also resulted in reduced ventricular dilatation and improved cardiac function.
LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery.
Background Heart failure (HF) with preserved ejection fraction (HFpEF) prevalence is increasing, and large clinical trials have failed to reduce mortality. A major reason for this outcome is the ...failure to translate results from basic research to the clinics. Evaluation of HFpEF in mouse models requires assessing three major key features defining this complex syndrome: the presence of a preserved left ventricular ejection fraction (LVEF), diastolic dysfunction, and the development of HF. In addition, HFpEF is associated with multiple comorbidities such as systemic arterial hypertension, chronic obstructive pulmonary disease, sleep apnea, diabetes, and obesity; thus, non-cardiac disorders assessment is crucial for a complete phenotype characterization. Non-invasive procedures present unquestionable advantages to maintain animal welfare and enable longitudinal analyses. However, unequivocally determining the presence of HFpEF using these methods remains challenging. Main text Transthoracic echocardiography (TTE) represents an invaluable tool in HFpEF diagnosis, allowing evaluation of LVEF, diastolic dysfunction, and lung congestion in mice. Since conventional parameters used to evaluate an abnormal diastole like E/A ratio, isovolumic relaxation time, and E/e' may pose limitations in mice, including advanced TTE techniques to characterize cardiac motion, including an assessment under stress, will improve diagnosis. Patients with HFpEF also show electrical cardiac remodelling and therefore electrocardiography may add valuable information in mouse models to assess chronotropic incompetence and sinoatrial node dysfunction, which are major contributors to exercise intolerance. To complete the non-invasive diagnosis of HF, low aerobic exercise capacity and fatigue using exercise tests, impaired oxygen exchange using metabolic cages, and determination of blood biomarkers can be determined. Finally, since HFpEF patients commonly present non-cardiac pathological conditions, acquisition of systemic and pulmonary arterial pressures, blood glucose levels, and performing glucose tolerance and insulin resistance tests are required for a complete phenotyping. Conclusion Identification of reliable models of HFpEF in mice by using proper diagnosis tools is necessary to translate basic research results to the clinics. Determining the presence of several HFpEF indicators and a higher number of abnormal parameters will lead to more reliable evidence of HFpEF. Keywords: Research, Echocardiography, Phenotype, Mouse models, Heart failure, Preserved ejection fraction
To learn about the experiences and opinions of adolescent non-consumers and regular cannabis users about cannabis use and the factors that determine its use, using the I-Change explanatory model as a ...basis.
Qualitative methodology with a content analysis was used. Focus groups were conducted with adolescents who were non-regular cannabis users (those who had not tried cannabis or had only experimented with it before) and semi-structured interviews were conducted with adolescent and young adult in recovery who were in a detoxification program. A deductive analysis of the audio-recorded and transcribed interviews was performed, using the domains of the I-Change Model as a reference.
Personal problems, social problems or family problems can lead to cannabis use. There was a lack of knowledge and low risk perception about consumption of this drug. There are other factors that influence consumption, the perception of advantages, such as the feeling of freedom and the influence of the peer group. The consumption of this substance in girls is changing, becoming more and more equal to that of boys. The family has an important role to play in preventing drug use.
Knowledge of these factors is of vital importance as a prior step to the development of efficient intervention measures adjusted to the needs identified and the characteristics of the population.
In this study we investigated the relationship between cognitive reserve (CR) proxies, such as education, physical activity (PA), and cognitive dysfunction (CD) in the presence or absence of ...frontotemporal disorders (FTD). Previous research has suggested that education and PA may delay the onset of CD and reduce the risk of developing dementia. However, it remains unclear whether these CR proxies can protect against CD when FTD is present. We aimed to explore this relationship and determine whether sustained CR may be evident regardless of FTD. We recruited 149 older adults (aged 65–99 years) from community centers where they were voluntarily participating in leisure activities. We used bioelectrical impedance to measure their body composition, and we administered the International PA Questionnaire and the Mini-Mental State Examination to measure their PA and cognitive function, respectively. We used the Frontal Assessment Battery to screen for frontotemporal dementia. Our results showed that people with FTD were older, had lower education, and engaged in less PA, relative to other participants. Regression models revealed that age, education, and PA were significant predictors of FTD. More specifically, FTD was negatively associated with cognitive functioning, and there were significant interaction effects between FTD and education and PA. PA and education were significant predictors of cognitive functioning, and, when values for PA and education were high, they offset the effects of FTD on cognitive function. These findings support impressions that PA and years of education provide an insulating or compensatory effect on cognitive functioning in older adults with executive dysfunction or frontotemporal dementia, highlighting the importance of encouraging both pursuits.
Nowadays the high nutritional value of whole grains is recognized, and there is an increasing interest in the ancient varieties for producing wholegrain food products with enhanced nutritional ...characteristics. Among ancient crops, einkorn could represent a valid alternative. In this work, einkorn flours were analyzed for their content in carotenoids and in free and bound phenolic acids, and compared to wheat flours. The most promising flours were used to produce conventional and sourdough fermented breads. Breads were in vitro digested, and characterized before and after digestion. The four breads having the best characteristics were selected, and the product of their digestion was used to evaluate their anti-inflammatory effect using Caco-2 cells. Our results confirm the higher carotenoid levels in einkorn than in modern wheats, and the effectiveness of sourdough fermentation in maintaining these levels, despite the longer exposure to atmospheric oxygen. Moreover, in cultured cells einkorn bread evidenced an anti-inflammatory effect, although masked by the effect of digestive fluid. This study represents the first integrated evaluation of the potential health benefit of einkorn-based bakery products compared to wheat-based ones, and contributes to our knowledge of ancient grains.
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